Arylsulfanyl and heteroarylsulfanyl derivatives for treating pain

ABSTRACT

According to the invention there is provided a compound the formula I; 
                         
wherein A, X, B, R 1 , R 2 , R 3  and R 4  are as defined in the specification.

BACKGROUND OF THE INVENTION

This application is a continuation of Ser. No. 11/445,424, filed on Jun.1, 2006, now U.S. Pat. No. 7,214,678 which is a continuation of Ser. No.10/938,792, filed on Sep. 10, 2004 now U.S. Pat. No. 7,098,223 which isa continuation of Ser. No. 10/232,264, filed Aug. 29, 2002, now U.S.Pat. No. 6,825,221 which application is based on, and claims the benefitof, U.S. Provisional Application No. 60/346,844, filed Oct. 18, 2001,and entitled ARYLSULFANYL AND HETEROARYLSULFANYL DERIVATIVES FORTREATING PAIN, and which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel, aromatic compounds andpharmaceutically-acceptable salts thereof which possess usefulpharmacological properties. More particularly the compounds of theinvention are antagonists of the pain enhancing effects of E-typeprostaglandins. The invention also relates to processes for themanufacture of the aromatic compounds and pharmaceutically-acceptablesalts thereof; to novel pharmaceutical compositions containing them; andto use of the compounds in pain relief.

DESCRIPTION OF THE RELATED ART

The compounds of the invention are useful in the treatment of pain suchas the pain associated with joint conditions (such as rheumatoidarthritis and osteoarthritis), post-operative pain, post-partum pain,the pain associated with dental conditions (such as dental caries andgingivitis), the pain associated with burns (including sunburn), thetreatment of bone disorders (such as osteoporosis, hypercalcaemia ofmalignancy and Paget's disease), the pain associated with sportsinjuries and sprains and all other painful conditions in which E-typeprostaglandins wholly, or in part, play a pathophysiological role.

Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the mainclasses of drugs in pain relief. However both possess undesirable sideeffects. NSAIDS are know to cause gastrointestinal irritation andopiates are known to be addictive.

Aromatic compounds which antagonize the pain-enhancing effects of E-typeprostaglandins are disclosed in U.S. Pat. Nos. 5,811,459; 5,834,458 and5,843,942. However, the need for compounds which relieve pain, withoutside effects, continues to exist.

BRIEF SUMMARY OF THE INVENTION

We have now found a class of compounds structurally different thanNSAIDS and opiates, and useful in the relief of pain.

The compounds of the invention may also possess antiinflammatory,anti-pyretic and anti-diarrheal properties and be effective in otherconditions in which prostaglandin E₂ (PGE₂) wholly or in part plays apathophysiological role.

According to the invention there is provided a compound the formula I;

wherein:

A is an optionally substituted: phenyl, naphthyl, pyridyl, pyrazinyl,pyridazinyl, pyramidal, thienyl, thiazolyl, oxazolyl or thiadiazolyl;

B is an optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl,thienyl, thiadiazolyl, isoxazole, pyrazole, furyl, pyrrolyl, imidazolyl,pyrazinyl, pyridazinyl, pyrimidyl, pyridone, pyrimidone, pyrazinone orpyridazinone;

X is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl or phenyl.

R¹ is CO₂H, CO₂R, COSO₂NR₂, tetrazolyl, P(O)(OR)₂ or SONH₂, wherein R ismethyl

R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₃ alkylaryl

R³ is H or C₁₋₅ alkyl

R⁴ is H or C₁₋₅ alkyl

Any of the above alkyl, alkenyl, alkynyl or aryl groups may optionallybe substituted.

Particular substituents for ring carbon atoms in A and X include halo,trifluoromethyl, nitro, hydroxy, amino, C₁₋₄alkylamino,diC₁₋₄alkylamino, cyano, C₁₋₆alkoxy, —S(O)_(p)C-₁₋₆ alkyl (wherein p is0, 1 or 2), C₁₋₆alkyl (optionally substituted by hydroxy, amino, halo,nitro or cyano), —S(O)_(p) CF₃ (wherein p is 0, 1 or 2), carbamoyl,C₁₋₄alkylcarbamoyl, di(C₁₋₄alkyl)carbamoyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₂₋₄alkenylamino, N—C₂₋₄alkenyl-N—C₁₋₄alkylamino, di-C₂₋₄alkenylamino,S(O)_(p) C₂₋₆alkenyl (wherein p is 0, 1 or 2), C₂₋₄alkenylcarbamoyl,N—C₂₋₄alkenyl-N-alkylamino, di-C₂₋₄alkenylcarbamoyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₃ alkyl, C₃₋₇cycloalkylC₂₋₃alkenyl, C₅₋₇cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₃alkyl, C₅₋₇cycloalkenylC₂₋₃alkenyl,C₅₋₇cycloalkenylC₂₋₃alkynyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoylamino,C₁₋₄alkanoyl(N—C₃₋₄alkyl)amino, C₁₋₄alkanesulphonamido,benzenesulphonamido, aminosulphonyl, C₁₋₄alkylaminosulphonyl,di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkanoyloxy,C₁₋₆alkanoyl, formylC₁₋₄alkyl, trifluoroC₁₋₃alkylsulphonyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆alkyl C₁₋₆alkylcarbamoylamino, oxazoly,pyridyl, thiazolyl, pyrimidyl, pyrazinyl and pyridazinyl.

Where a ring nitrogen atom in A can be substituted without becomingquaternised, it is unsubstituted or substituted by C₁₋₄alkyl.

Particular substituents for ring carbon atoms in B include halo, amine,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, trifluoromethyl, nitro, hydroxy,C₁₋₆alkoxy, C₁₋₆ alkyl, cyano, —S(O)_(p)C₁₋₆ alkyl (wherein p is 0, 1 or2), carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

Where a ring nitrogen atom in B can be substituted without becomingquaternised, it is unsubstituted or substituted by C₁₋₄ alkyl.

Preferably A is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl,pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl.

More preferably A is phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl orpyimidyl.

Most preferably A is phenyl or thienyl.

In particular A is phenyl.

Preferably B is pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl,thiadiazolyl, imidazolyl, pyrazinyl, pyrimidyl, or oxazolyl.

More preferably B is pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl oroxazolyl.

Yet more preferably B is pyridyl, phenyl, thienyl, pyridazinyl orthiazolyl.

Yet more preferably B is phenyl, pyridyl or pyridazinyl.

Most preferably B is pyridyl.

Preferably X is pyridyl, thienyl, thiazolyl, furyl or phenyl.

Most preferably X is phenyl.

Preferably R¹ is selected from the group consisting of CO₂H and CO₂R,e.g. CO₂H.

Preferably R² is selected from the group consisting of H and C₁₋₆ alkyl,e.g. C₁₋₆ alkyl.

Preferably R³ is H.

Preferably R⁴ is H.

BRIEF DESCRIPTION OF THE DRAWING FIGURE

The FIGURE is a schematic of the chemical synthesis of6-[(2-Benzylsulfanylbenzyl)ethyl amino]nicotinic acid, a preferredcompound of the present invention. In the FIGURE, the numbers correspondto the numbering of the Examples.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that, insofar as certain of the compounds offormula (I) defined above may exist in optically active or racemicforms, by virtue of the compounds of the formula (I) containing anasymmetric carbon atom, the invention includes in its definition ofactive ingredient any such optically active or racemic form whichpossesses pain relieving properties. The synthesis of optically activeform may be carried out by standard techniques of organic chemistry wellknown in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form. Similarly, painrelieving properties may be evaluated using the standard laboratorytechniques referred to hereinafter.

As stated hereinbefore compounds of the formula (I) are antagonists ofthe pain enhancing effects of E-type prostaglandins and of value in therelief of pain which, for example, accompanies inflammatory conditionssuch as rheumatoid arthritis and osteoarthritis. Certain properties ofthe compounds may be demonstrated using the test procedures set outbelow:

(a) an in-vitro guinea pig ileum assay which assesses the inhibitoryproperties of a test compound against PGE₂-induced contractions of theileum; ileum was immersed in oxygenated Krebs solution containingindomethacin (4 μ/ml) and atropine (1 μM) and which was maintained at37° C.; the ileum was subject to a tension of 1 g; a control doseresponse curve for PGE₂-induced contraction of the ileum was obtained;test compound (dissolved in dimethylsulphoxide) was added to the Krebssolution and a dose response curve for the PGE₂-induced contraction ofthe ileum in the presence of the test compound was obtained; the pA₂value for the test compound was calculated;

(b) an in-vitro assay in mice which assesses the inhibitory propertiesof a test compound against abdominal constriction response induced bythe intraperitoneal administration of a noxious agent such as diluteacetic acid or phenylbenzoquinone (hereinafter PBQ) using the proceduredisclosed in European Patent Application No. 0218077.

Prostaglandin receptors and in particular receptors for PGE₂ have beententatively characterised by Kennedy et al. (Advances in Prostaglandin,Thromboxane and Leukotriene Research, 1982, 11, 327). The known PGE₂antagonist SC-19220 blocks the effect of PGE₂ on some tissues such asguinea pig ileum or dog fundus but not on other tissues such as the cattrachea or chick ileum. Those tissues which did posses SC-19220sensitive mediated effects were said to possess EP₁ receptors. Based onthis compound of the present invention, possessing activity in Test (a),are EP₁ antagonists.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a compound of the formula (I)or an in-vivo hydrolysable ester thereof or an amide thereof, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, suspension oremulsion; for topical use, for example a cream, ointment, gel, spray oraqueous or oily solution or suspension; for nasal use, for example asnuff, nasal spray or nasal drops; for vaginal or rectal use, forexample a suppository or rectal spray; for administration by inhalation,for example as a finely divided powder or a liquid aerosol; forsub-lingual or buccal use, for example a table or capsule; or forparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilsolution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is a compound of the formula (I)or a pharmaceutically-acceptable salt thereof) that is combined with oneor more excipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

According to a further feature of the invention there is provided acompound of the formula (I) or an in-vivo hydrolysable ester or amide ora pharmaceutically-acceptable salt thereof, for use in a method oftreatment of the animal (including human) body by therapy.

According to a further feature of the invention there is provided amethod for the relief of pain in the animal (including human) body inneed of such treatment which comprises administering to said body aneffect amount of a compound of the formula I, or an in-vivo hydrolysableester or amide or a pharmaceutically-acceptable salt thereof.

As mentioned above, a compound of the formula (I) is useful in treatingthe pain which, for example, accompanies inflammatory conditions such asrheumatoid arthritis and osteoarthritis. In using a compound of theformula I for therapeutic or prophylactic purposes it will generally beadministered so that a daily dose in the range, for example, 0.1 mg to75 mg per kg body weight is received, given if required in divideddoses. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, 0.05 mg to 30 mg per kg body weight willgenerally be used. Similarly, for administration by inhalation, a dosein the range, for example, 0.05 mg to 25 mg per kg body weight will beused.

By virtue of their ability to relieve pain, the compounds of the formulaI are of value in the treatment of certain inflammatory andnon-inflammatory disease which are currently treated with acyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID)such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen,sulindac, tolmetin and piroxicam. Co-administration of a compound of theformula I with a NSAID can result in a reduction of the quantity of thelatter agent needed to produce a therapeutic effect. Thereby thelikelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced.

The compounds of the invention may also be used with otheranti-inflammatory agents such as an inhibitor of the enzyme5-lipoxygenase (such as those described in European Patent ApplicationsNos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662,0385663, 0385679, 0385680.)

The compounds of the formula (I) may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegenerative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compositions of the invention may in addition contain one or moreother therapeutic or prophylactic agents known to be of value for thetreatment of pain. Thus for example, a known opiate pain-killer (such asdextropropoxyphene, dehydrocodeine or codeine) or an antagonist of otherpain or inflammation mediators, such as bradykinin, takykinin andcalcitonin gene related peptides (CGRP), or an alpha₂adrenoceptoragonist, a GABA_(b) receptor agonist, a calcium channel blocker, asodium channel blocker, a CCK_(b) receptor antagonist, a neurokininantagonist or an antagonist and modulator of the action of glutamate atthe NMDA receptor may usefully also be present in a pharmaceuticalcomposition of the invention.

The compounds of the present invention may also be administered in bonediseases such as osteoporosis with calcitonin and bisphosphonates.

The invention is further illustrated by the following non-limitingExamples which are summarized in the reaction scheme of FIG. 1, whereinthe compounds are identified by the same designator in the Examples andFIG. 1.

EXAMPLE 1 Thiosalicylic acid (1)

Thiosalicylic acid was purchased from Aldrich Chemical Co., Inc.,Milwaukee, Wis. 53233 USA.

EXAMPLE 2 2-Benzylsulfanyl benzoic acid benzyl ester (2)

A solution of thiosalicylic acid 1 (2.0 g, 13.0 mmol) in 13 mL ofacetone was treated with 1, 8-Diazabicyclo[5.4.0]undec-7-ene (7.8 mL, 52mmol) and benzylbromide (6.2 mL, 52 mmol). The reaction was stirred atroom temperature for 50 minutes. The mixture was concentrated undervacuum to remove the acetone. Water was added and the mixture wasextracted with EtOAc (3×). The organic layer was washed with water,brine, dried over MgSO₄, filtered and concentrated in vacuo to give ayellow solid without purification.

EXAMPLE 3 2-Benzylsulfanyl benzoic acid (3)

To a suspension of 2-benzylsulfanyl benzoic acid benzyl ester 2 (113 mg,0.34 mmol) was added 1.6 mL of 1N NaOH. KOH (1 pellet) was added and thereaction was continued overnight. The acetone was removed and a smallamount of water was added. The aqueous solution was washed with CH₂Cl₂(3×). The aqueous phase was acidified until pH of 2-3 was reached thenextracted with CH₂Cl₂ (3×), dried with MgSO₄ and filtered andconcentrated to give a white solid.

EXAMPLE 4 (2-Benzylsulfanylphenyl)methanol (4)

To a solution of 2-benzylsulfanyl benzoic acid 3 (50 mg, 0.206 mmol) inTHF at 0° C. was added LiAlH₄ (0.62 mL of a 1.0 mL solution in THF, 0.62mmol) and the mixture was stirred at 0° C. for 15 minutes then allowedto warm to room temperature. The solution was stirred for 2 hours. Themixture was cooled at 0° C. then methanol (MeOH) was added slowlyfollowed by HCl (0.5N) and tetrahydrofuran (THF). The mixture wasstirred at room temperature for 30 minutes. It was then concentrated toremove THF, extracted with CH₂Cl₂ (3×), dried over MgSO₄, filtered andconcentrated to give 30 mg of the product as a yellow oil.

EXAMPLE 5 2-(2-Bromomethylphenylsulfanylmethyl)benzene (5)

A solution of (2-Benzylsulfanyl)methanol 4 (120 mg, 0.522 mmol) inanhydrous Et₂O was cooled to 4° C. A solution of PBr₃ (49 μL, 0.52 mmol)in anhydrous Et₂O was added dropwise, keeping the temperature below 10°C. The reaction was allowed to warm to ambient temperature and stirredfor one hour. The reaction was filtered through silica gel (2.0 g) andwashed with Et₂O. The filtrate was washed with H₂O saturated aqueoussodium bicarbonate and brine. The organic layer was dried over Na₂SO₄,filtered and evaporated to give 95 mg of the named product as a yellowoil.

EXAMPLE 6 6-[(2-Benzylsulfanylbenzyl)ethylamino]nicotinic acid methylester (6)

A solution of methyl-6-ethylaminonicotinate in (59 mg, 0.332 mmol) DMF(0.8 mL) was added to sodium hydride (12 mg, 0.293 mL) in DMF (0.8 mL)at 0° C. The reaction was stirred for 1 hour and a solution of2-(2-bromomethylphenyl sulfanylmethyl) benzene 5 (81 mg, 0.276 mmol) in80 μL of DMF was added. The reaction was allowed to warm to ambienttemperature and stirred for 18 hours. The solution was quenched withwater and extracted with EtOAc (7×). The organic layers were combined,washed with water and brine twice, dried over MgSO₄ and evaporated togive a white solid that was recrystallized from EtOAc/hexane. The solidwas purified with 5% EtOAc/hexane by chromatography to yield 350 mg(70%) of the named compound.

EXAMPLE 7 6-[(2-Benzylsulfanylbenzyl)ethylamino]nicotinic acid (7)

To a solution of the ester of Example 6 in THF (0.8 mL) was added asolution of KOH (14 mg, 0.255 mmol) in H₂O (0.2 mL). The mixture wasstirred at 50° C., then concentrated to remove THF. The aqueous phasewas washed with ethyl ether, then the aqueous phase was acidified untilpH 3-4 was reached. The acidified solution was extracted with Et₂O orEtOAc (3×), dried over MgSO₄, filtered and concentrated in vacuo to givea white solid.

The compounds of Examples 6 and 7 represent the compounds of the presentinvention wherein A is phenyl, B is pyridyl and X is phenyl. The othercompounds of the invention may be prepared by substituting theappropriate reactant(s) and carrying out the reactions illustrated inExamples 1 through 7 and Scheme 1 of the Drawing FIGURE. For example,the compounds of the present invention wherein B is phenyl may beprepared by use of methyl-6-ethylaminobenzoate for methyl-6-ethylaminonicotinate in the method of Example 6. In the compounds of the inventionwherein A is pyridyl, 2-(2-Bromomethylpyridylsulfanylmethyl)benzene maybe substituted for 2-(2-Bromomethylphenyl sulfanylmethyl)benzene (5) inthe method of Example 6. In the compounds of the present inventionwherein X is thienyl, 2-(2-Bromomethylphenylsulfanylmethyl)thiophene maybe substituted for 2-(2-Bromomethylphenyl sulfanylmethyl)benzene (5) inthe method of Example 6.

EXAMPLE 8 Alleviation of Chronic Pain

A model for chronic pain (in particular peripheral neuropathy such ascausalgia) involves the surgical ligation of the L5 (and optionally theL6) spinal nerves on one side in experimental animals. Rats recoveringfrom the surgery gain weight and display a level of general activitysimilar to that of normal rats. However, these rats developabnormalities of the foot, wherein the hindpaw is moderately everted andthe toes are held together. More importantly, the hindpaw on the sideaffected by the surgery appears to become sensitive to pain fromlow-threshold mechanical stimuli, such as that producing a faintsensation of touch in a human, within about 1 week following surgery.This sensitivity to normally non-painful touch is called “tactileallodynia” and lasts for at least two months. The response includeslifting the affected hindpaw to escape from the stimulus, licking thepaw and holding it in the air for many seconds. None of these responsesis normally seen in the control group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra Xlll down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, six rats per test group are administered the testdrugs by intraperitoneal (i.p.) injection or oral gavage. For i.p.injection, the compounds are formulated in approximately 50% DMSO andgiven in a volume of 1 ml/kg body weight. The compound of Example 7 wastested at doses ranging between 30 and 3000 ng/kg. A volume equal to 1ml/kg body weight of an appropriate concentration (i.e.. 1 mg/ml for a 1mg/kg dose) of the compound of Example 7 formulated in approximately 50%DMSO was injected using an 18-gauge, 3-inch gavage needle that is slowlyinserted through the esophagus into the stomach.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980). The post-drug threshold iscompared to the pre-drug threshold and the percent reversal of tactilesensitivity is calculated based on a normal threshold of 15.1 grams. Thecompound of Example 7 was able to reduce the response to the tactilestimuli that indicate tactile allodynia. Compared to a saline solution,this compound reversed the allodynic pain by 25% at an i.p. dose of 100ng/kg, 60% at 300 ng/kg, 90% at 100 mg/kg and 92% at 3000 ng/kg.

In comparison, when 6-[(2-Benzyloxy-5-bromobenzyl)ethylamino]nicotinicacid is tested in this pain model allodynic pain was reversed 10% at ani.p. dose of 30 ng/kg, 50% at 100 ng/kg, 55% at 300 ng/kg and 60% atng/kg.

When the following compounds of the invention are substituted for6-[(2-Benzylsulfanylbenzyl)ethylamino]nicotinic acid (7), in Example 8,it is believed that tactile sensitivity will be reduced:

6-[2-Benzylsulfanylbenzyl)ethylamino]benzoic acid or the methyl esterthereof.

6-[2-Pyridylsulfanylbenzyl)ethylamino]nicotinic acid or the methylesterthereof.

6-[2-Benzylsulfanylthienylmethyl)ethylamino]nicotinic acid or themethylester thereof.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound of the formula I

wherein A is selected from the group consisting of optionallysubstituted: pyridyl, pyrazinyl, pyridazinyl, pyramidal, thienyl,thiazolyl, oxazolyl and thiadiazolyl; B is selected from the groupconsisting of optionally substituted: pyridyl and pyridone; X isselected from the group consisting of optionally substituted: pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,and phenyl; R¹ is selected from the group consisting of is CO₂H, CO₂RCOSO₂NR₂, tetrazolyl, P(O)(OR)₂ and SONH₂, wherein R is Me; R² isselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl and C₁₋₃ alkylaryl; R³ is selected from the group consisting ofH and C₁₋₅ alkyl and R⁴ is selected from the group consisting of H andC₁₋₅ alkyl.
 2. The compound of claim 1 wherein R¹ is selected from thegroup consisting of CO₂H and CO₂R.
 3. The compound of claim 1 wherein R¹is COOH.
 4. The compound of claim 1 wherein R² is selected from thegroup consisting of H and C₁₋₆ alkyl.
 5. The compound of claim 1 whereinR² is C₁₋₆ alkyl.
 6. The compound of claim 1 wherein R³ is H.
 7. Thecompound of claim 1 wherein R⁴ is H.
 8. A pharmaceutical compositionwhich comprises a compound according to claim 1 and apharmaceutically-acceptable carrier.